2-thiono-5-oxazolidones



Patented Aug. 18, 1953 -miitc-aoxiizcmijon"" George E'." Bennett sea-Joann" manage assignors to Monsanto fihe'inicallCo lnpany; St; Louis, Mo., a corporation'o'f Delaware No Drawing. Applicatioiig ipr il 1 951,

Serial N0. 223,831

6' Claims; 1-

This invention relates to'eliiii'r'cla's's of protein intermediates. More specifically the invention relates to a usefulcl "of amino' afc'idl pleri eves which r a ti vv aim. v. amnesia thesis of p'olypeptides'and" other proteinpoly mers.

It is well-known that fot'ein s: thesized from amino acid s." Furthermore In th ods of converting amino acids into more tive derivatives are used are 'ltatjethep y merization and interpdlyrherigatlon stps flfhes'e more reactive derivatives, for exam ne;- tlie N- carboxy anhydrides which are otherwise known as 2,5-oxazolidinediones, are often so sensitive to moisture that they cannot be stored except under strictly anhydrous conditions. This property of the intermediates greatly restricts the practical application of the reaction in the preparation of polypeptides. p

The principal purpose of v this invention is' fto provide a class of stableijnterme'diates" which are much less reactive withmoisturevapor than are the N-carboxy anhydrides A further pose is to provide a novelj ho pre ing polypeptides. A still fu" he purp'os' forth is" invention is to provide a he s o'faminoac'id derivatives hereinafter descr n It has been found that the 2-thiond "arogueg of the various N-carboxyamino acid nhydridels' are unusually stable under c'ondit ns' favor the rapid decomposition of t anhydrides. The newthiono'pompo represented by the generic structuralformiilai R. R-(IJC=O wherein R is a radical of the group consisting of hydrogen, alkyl and aralkyl, and R is a radical of the group consisting of hydrogen and methyl.

The new chemical compounds may be prepared from the corresponding amino acids by first reacting them with an ester of thionochloroformic acid and thereafter treating the resulting N-thiono esters of the amino acids with thionyl chloride or phosphorus pentachloride. The first of these reactions is conducted at room temperature in solution in a suitable anhydrous solvent. The second step may involve the reaction of thionyl chloride on the solid intermediate or the reaction between the intermediate and phosphorus pentachloride in a suitable inert solvent. The latter reaction may also be accomplished at room temperature or slightly above. Upon removing the solvents and/or excess reagents by warming under reduced pressures, the

hi i sw a a amino acids or salts thereof the desire'djcom' pounds can be obtained directly. The reaction from (glycine) 2' -thione -fi oxazolidone cng-cn c= o (from alanine) 4 methyl-Z-thiono 5 Q oxazolidone O Ha CIICH-O=O e g NE 5 (train? vaiiii) capital-24mins: 5 may idone CH3-OHCHaCH-C=0 CH3 11113: (I)

(from leucine) 4-isobutyl-2-thiono 5 oxazolidone The new compounds are useful as intermediates in the preparation of a variety of chemical products. Polypeptides, both polymers and copolymers of the amino acids can be readily prepared from the intermediates, and in this form, are useful as foodstuffs, pharmaceuticals or as raw materials in the fabrication of films and fibers.

Further details of the invention are set forth with respect to the following examples:

Example 1 A 500 -ml., three-necked flask, provided with a mechanical stirrer, a thermometer, and a drying e by" reaction r which' with the tube was charged with 35.5 grams of N-carbothionomethoxy-e-aminoisobutyric acid and 200 ml. of ether. The mixture was cooled to C. and 52.1 grams of phosphorus pentachloride was added in increments at a rate which permitted the maintenance of a temperature below C. As the reaction proceeded a solid product was precipitated. The resulting suspension was then treated with 100 ml. of dry ethyl acetate to form.

4,4-dimethyl-2-thiono-5-ox-azolidone with the structure:

CH3CO=O Example 2 Using the apparatus described in the preceding example, 91 grams of N-carbothionomethoxyphenylalanine was reacted with 110 ml. of thionyl chloride for 30 minutes at room temperature and then for fifteen minutes at 40 C. The excess thionyl chloride was removed by applying an aspirator pressure at 40 C. for one hour and then at 60 C. to 65 C. until further heating produced no reduction in weight. The residue was dissolved in acetone and treated with activated charcoal. The solution was evaporated to dryness and the product identified as 4-benzyl-2- thiono-5-oxazolidone having the following structural formula:

Example 3 4 non-thio compound, 4,4-dimethyl-2,5-oxazolidinedione, was demonstrated by exposing 0.5 gram samples to moisture-saturated air in a closed vessel; at room temperatures. After exposure of the samples for pre-determined periods of time, the

acetone insoluble contents of the samples were measured. The following table sets forth the observed data:

Acetone Insoluble Content Time (Hours) Th derivative Control The above data demonstrate that in sixty-nine hours only 1.4 percent of the thiono compound decomposed spontaneously, Whereas in excess of per cent of the control compound, the 4,4-dimethyl-2,5-oxazolidinedione, was decomposed.

The invention is defined by the following claims.

What we claim is:

lQAs a new chemical compound, the amino acid derivative having the structural formula:

wherein R is a radical-of the group consisting of hydrogen, lower alkyl and benzyl and R, is a radical of the group consisting of hydrogen and methyl.

2. As a new chemical compound, 4,4-dimethyl- 2-thiono-5-oxazolidone.

3. As a new chemical compound, 4-benzyl-2- thiono-5-oxazolidone.

4. As a new chemical compound, 2-thiono-5- oxazolidone.

5. As a new chemical compound, 4-isopropyl-2- thiono-S-oxazolidone.

6. As a new chemical compound, 4-isobutyl-2- thiono-5-oxazolidone.

GEORGE E. BENNETT. JOHN B. O-TT.

References cited. Rouiller, C. A., vol. 14 (1920.) page 47. 

1. AS A NEW CHEMICAL COMPOUND, THE AMINO ACID DERIVATIVE HAVING THE STRUCTURAL FORMULA: 